Blood First Edition Paper, prepublished online March 23 ... · PDF file1 Charlotte...
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How I treat common variable immune deficiency
C. Cunningham-Rundles MD PhD 1
1 Mount Sinai School of Medicine, Department of Medicine, New York City,
New York.
1 Charlotte Cunningham-Rundles MD PhD
David S Gottesman Professor of Immunology
Mount-Sinai Medical Center
1425 Madison Avenue
New-York City, New York 10029
Phone 212 659 9268
Fax 212 987 5593
E-mail [email protected]
Blood First Edition Paper, prepublished online March 23, 2010; DOI 10.1182/blood-2010-01-254417
Copyright © 2010 American Society of Hematology
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Abstract:
Common variable immunodeficiency (CVID) is a rare immune deficiency,
characterized by low levels of serum IgG, IgA and/or IgM, with loss of antibody
production. The diagnosis is most commonly made in adults between the ages
of 20 and 40, but both children and older adults can be found to have this
immune defect. The range of clinical manifestations is broad, including acute
and chronic infections, inflammatory and autoimmune disease and an increased
incidence of cancer and lymphoma. For all these reasons, the disease
phenotype is both heterogeneous and complex. Contributing to the complexity is
that patient cohorts are generally small, criteria used for diagnosis vary, and the
doses of replacement immune globulin differ. In addition, routines for monitoring
patients over the years and protocols for using other biologic agents for
complications have not been clarified or standardized. In the past few years,
data from large patient registries have revealed that both selected laboratory
markers and clinical phenotyping may aid in dissecting groups of subjects into
biologically relevant categories. This review presents my approach to the
diagnosis and treatment of patients with CVID, with suggestions for the use of
laboratory biomarkers and means of monitoring patients over time.
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Introduction:
CVID is the most common clinically important primary immune deficiency
disease due to a prevalence, estimated at between 1 in 25,000 to 50,000
Caucasians, complications, hospitalizations and requirement for lifelong
replacement immune globulin therapy(1, 2). Unlike many genetic immune
defects, the majority of subjects diagnosed with CVID are adults between the
ages of 20 and 40 years, although many are found outside this age range.
Although the syndrome was first described more than 50 years ago(3), the
diagnosis is still commonly delayed by 6-8 years, even after the onset of
characteristic symptoms. A number of reports of cohorts of subjects with CVID
have appeared(1, 4-8). In appropriate doses, immunoglobulin (Ig) replacement
reduces the incidence of acute bacterial infections, however, Ig does not
address the more problematic of complications that have now emerged as the
foremost concerns, including chronic lung disease, systemic granulomatous
disease, autoimmunity, lymphoid hyperplasia and infiltrative disease,
gastrointestinal disease, and the development of cancer. These complications
now appear to be the major cause of morbidity and death in CVID(1, 9). This
review is intended as a personal summary of how I assess patients at the
outset, and outline how one may monitor for and treat some of these
challenging complications.
Diagnosis of CVID: The diagnosis of common variable immune deficiency
(CVID, International Classification of Diseases code, ICD 279.06) is often
misused. It is defined as a genetic immune defect characterized by
significantly decreased levels of IgG, IgA and/or IgM with poor or absent
antibody production, with exclusion of genetic or other causes of
hypogammaglobulinemia(1, 2, 9, 10). Based on the standard definition,
antibody deficiency with normal immune globulin levels, or IgG deficiency
alone, would not qualify for the diagnosis of CVID. As CVID is not always
easily discerned from transient hypogammaglobulinemia of infancy, a general
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consensus is that this diagnosis should not be applied until after the age of 4.
This allows time for the immune system to mature, and if necessary, to
consider the possibility of other genetic primary immune defects. However, the
published criteria still leave open rather wide boundaries. First laboratory
standards for normal ranges differ; in addition, using the 95% percentile for
immune globulins, allow 2.5% of normal subjects to fall below the normal
range. Sometimes forgotten, the additional necessary criteria for CVID also
include a proven lack of specific IgG antibody production. This is usually
demonstrated by lack of IgG responses (not attaining laboratory-defined
protective levels) to two or more protein vaccines such as tetanus or diphtheria
toxoids, Haemophilus conjugate, measles, mumps and rubella vaccines, and
also by lack of response to pneumococcal polysaccharide vaccines. Other
options for protein antigens include hepatitis A or B vaccines or varicella,
either after vaccination or disease exposure. Examining blood for pertinent
isohemagglutins, is another a common means of testing (mostly) IgM anti-
carbohydrate antibody production in older children and adults. While extensive
antibody testing is not as important for subjects with very low serum IgG
(potentially 150 mg/dl or less), those with higher levels of serum IgG (450-
600mg/dl) and especially those with only minimally reduced serum IgA, require
more extensive evaluation. It is more likely that these subjects have
preservation of IgG antibody production and are therefore less likely to benefit
from Ig therapy. A suggested template for such analyses is given on Table 1.
Demonstration of persistence of IgG antibody at 6 months after vaccination
can be important to prove sustained antibody production in some cases. The
many reasons for a very thorough evaluation before diagnosing CVID, include
the facts that the diagnosis of CVID impacts short and long term insurance
coverage, influences the outcome of all subsequent medical encounters, and
may alter school and job choices and other life decisions, i.e. family planning
and travel. In addition, if replacement Ig therapy is initiated without a compete
evaluation and the use of this therapy is later questioned, it must be stopped
for about 5 months before such an evaluation can be performed.
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Immune globulin replacement: The primary treatment of CVID is
replacement of antibody, achieved by either intravenous (IV) or subcutaneous
(SQ) route of immune globulin (Ig), usually in doses of 400 to 600 mg/kg body
weight a month (11). This dose is usually divided into once or twice a week, or
every 2 weeks (for SQ) or every 3 or 4 weeks (IV.) The original calculation for
the half-life of IgG of 21 days was based on iodinated IgG protein(12), but
current IV Igs have a half lives closer to 30 days(13) (14-16) suggesting that
original estimations might be inaccurate due to protein modification. However,
the half-life in individual patients may vary considerably for not entirely clear
reasons. Administered IgG in CVID subjects with chronic lung or
gastrointestinal disease appears to have a shorter half-life. In addition, biologic
variations in the abundance of the neonatal Fc receptor(17) might impact IgG
turnover.
The goal of Ig therapy is to prevent infections, however, the target trough
serum IgG to attain, varies depending on the baseline level of IgG. For a
subject with a baseline serum IgG of less than 100 mg/dl, a suggested trough
level would be at least 600 mg/dl, but for a subject with an initial IgG of 300
mg/dl with no functional antibody, the required trough level might be 900 mg/dl
to supply the minimum “normal” level of functional Ig. Immune globulin is often
given in the home. Both IV and SQ methods provide both safe and effective
replacement(18) (19) (11); convenience to the patient can best guide these
choices. In our practice, the majority of our patients are given 400 mg/dl IV
once per month; 10 to 15% are using SQ treatment in pro-rated doses given
more frequently. Attention is given to those with lung disease or previous
autoimmunity to be sure that more than adequate “trough” levels are
maintained. By definition, most patients with CVID have little or no serum IgA;
while anti-IgA antibodies have been reported(20), these are quite rare, and
from a pragmatic point of view, determining if IgG anti-IgA is present is not
clinically important. I am opposed to the use of indwelling ports as these mark
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patients as medically impaired, provide known risks of infection, and in any
case, need replacing with time. Poor IV access can be addressed using the
SQ route, dividing the required monthly dose into biweekly, or weekly doses.
On stable doses of replacement Ig, patients on Ig therapy can be adequately
followed, measuring trough serum IgG levels at 6 to 12-month intervals.
Complications and Management: The commonest clinical history in CVID
includes frequent infections in most but not all subjects. The respiratory tract is
most commonly involved, occurring in up to 73% of patients with pneumonia
due to Streptococcus pneumonia, Haemophilus influenza, or mycoplasma
species being the most prevalent condition before diagnosis(21) (6) (5, 8).
Severe bacterial infections such as empyema, sepsis, meningitis, or
osteomyelitis, often with the same organisms, are less common but are noted
in all series. In our current cohort, 90% of 476 subjects have had one or more
of these infectious complications. However, subjects with CVID have other
less well understood inflammatory, autoimmune or neoplastic conditions, as
outlined for our cohort, on Table 2. While the incidence of these complications
appear to vary in different countries,(1) they appear in all cohorts so far
examined. The ramifications and treatment of these complications are
described below.
Chronic Lung Disease: While pneumonia is clearly much less common after
adequate Ig replacement is initiated(22), continued respiratory tract disease
even after treatment is instituted, can lead to obstructive, restrictive,
bronchiectatic changes in some cases (8). Parenchymal and interstitial
changes include nodules on high resolution CT (HRCT) scans, reticular
changes, fibrosis and/or ground glass appearance. For larger or persistent
nodules, biopsy may be require to determine if these are scars, lymphoid
collections of possibly clonal cells or granulomatous infiltrates. Continued lung
damage can lead to substantial morbidity, in the more severe cases,
necessitating continuous oxygen treatment and/or heart or lung transplantation
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(10). It is unclear whether such a downward spiral is due to previous lung
damage that is difficult to reverse, continued low-grade infections that are not
adequately addressed by replacement Ig, ongoing inflammatory changes due
to immune dysregulation, or a combination of all of these factors. The
microbiology of the lungs may also include organisms potentially not
susceptible to antibody clearance, including the most prevalent organism, non-
typeable H. Influenzae, and/or viruses(23). Higher doses of Ig (600
mg/kg/month) may help to prevent infections and possibly chronic lung
disease(24, 25) but no controlled trials have been conducted to select which
patients would benefit, and what doses of Ig would be needed. In my view, for
continued lung disease, daily antibiotic prophylaxis (trimethoprim sulfa, or
possibly better, macrolides, which provide substantial anti-inflammatory
effects(26)) provide more benefit than much higher doses of Ig therapy. While
rotating antibiotics to discourage resistant organisms are often used in immune
competent individuals with chronic lung disease, I have not found it necessary
to rotate antibiotics in CVID; resistant organism can be treated if they arise.
Granulomatous/ lymphoid infiltrative disease: Localized or systemic
granulomatous disease, sometimes erroneously called “sarcoidosis,” occurs in
between 8 to 22% of subjects with CVID (10, 27-32) The granulomatous
changes may be diagnosed years prior to the recognition of
hypogammaglobulinemia and may in these cases delay the recognition of the
immune defect because the diagnosis of sarcoidosis is assumed to be
established. Lungs, lymph nodes and spleen are the more commonly affected
sites, although the skin, liver, bone marrow, kidney, gastrointestinal tract and
brain may be involved (27, 33-35). The granuloma in CVID are variously well-
formed, non caseating, and may contain contain non-necrotizing epithelioid
and giant cells. While organisms are sought, these are very rarely found. In
our series of 37 patients, 8.1% of our CVID subjects, the median age at
diagnosis of CVID was 26 (2 - 59). 14 had granulomas 1 - 18 years before
diagnosis of CVID; in 6 the detection of granulomas coincided with this
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diagnosis; for 17, granulomas were documented later. 54% had lung
granulomas, 43% in lymph nodes and 32% in liver (31). For unclear reasons,
subjects with granulomatous disease are also much greater risk for
autoimmune disease (almost always immune thrombocytopenia or
autoimmune hemolytic anemia) than CVID subjects who do not have this
pathology; for example, 54% of our patients with known granulomatous
disease have had autoimmune disease. As described below, these subjects
are also almost always those who have very few circulating, isotype switched
memory B cells (36). In some of these patients, an intense lymphoid infiltration
accompanies the granulomas in lungs, leading to what has been termed
“granulomatous lymphocytic interstitial lung disease,” (29, 37) the presence of
which is prognostic of a poor outcome (37). A recent study reported a median
survival of 13.7 years in CVID patients with granulomatous/lymphoid interstitial
infiltrates, as compared to 28.8 years in those without this complication (29).
HHV8 has been proposed to play a role of in the development of
granulomatous disease in CVID (38) but this is still to be confirmed. No case
control studies have been performed to define the most effective treatment of
granulomatous disease in CVID. Oral steroids in doses of 10mg a day or 20mg
every other day may preserve lung or liver function, realizing that this presents
a risk for infections and other undesirable side effects. For long term therapy, I
prescribe 200-400 mg a day (or range 3.5 to 6.5 mg/kg) of hydroxycloroquine,
based on its mechanistic roles in reducing toll like receptor responses, antigen
presentation, and its use in autoimmunity and sarcoidosis (39, 40). For
pulmonary granuloma, twice daily-inhaled beclomethasone is also prescribed.
Higher doses of IVIG have been found in one instance to aid in controlling
lymphoid interstitial disease and granuloma (41, 42) but this does not seem to
be a universal experience. Some years ago, work showed that some CVID
patients had elevated serum levels of TNF-alpha and soluble TNF
receptors(43). Later, Mullighan reported granuloma in 20 of 90 patients with
CVID (22%); 8 of these had an unusual TNF-alpha allele (TNF +488A)(28),
but TNF- alpha production or levels were not actually examined. On this basis,
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and suggestive earlier work in sarcoidosis, TNF-alpha inhibitors (infliximab or
etanercept) have been used in subjects with CVID with granuloma, with benefit
in some cases (35, 44, 45); however, no controlled trials have been
performed. I have had limited experience using TNF inhibitors for
granulomatous disease; in 2 cases (both with granuloma in lung) it was not
helpful but both patients had substantial lung defects.)
Lymphoid infiltrates in the lung leading to lymphoid interstitial pneumonia or
follicular bronchitis/bronchiolitis without granuloma are equally challenging, as
these lead to cough, shortness of breath, alveolar damage and ultimately, the
need for oxygen therapy. Due to scarring and the predominance of T cells in
the lung infiltrate (as shown in Figure 1,) cyclosporine has also been used with
benefit (125 mg a day; serum level 76ng/ml) (46). We have used cyclosporine
in two subjects, with some stabilization of lung function for 4 years, but both
succumbed to respiratory insufficiency, complicated by fatal acute hemolytic
anemia in one of these subjects (31).
Autoimmunity: Other complications resulting from immune dysregulation in
CVID include autoimmune disease in up to 25%, mostly immune
thrombocytopenia purpura (ITP), autoimmune hemolytic anemia (AIHA) or
both (Evans syndrome) or more rarely, autoimmune neutropenia (47, 48).
(Table 3) CVID subjects with ITP or Evans syndrome tend to be younger than
those who developed AIHA (49). This group of subjects are also likely to have
very few isotype switched memory B cells in peripheral blood (36). As we have
found that more episodes of recurrent episodes of ITP and/or AIHA occur
before replacement Ig treatment is started than afterward, Ig in these doses
may exert a protective effect (49). Higher doses of Ig (1g/kg body weight)
given weekly for a short time can be used to supplement baseline therapy if
autoimmune disease persists. Intravenous steroids (1 gram
methylprednisolone) followed by moderate doses of oral steroids tapered over
several weeks or more, will also often resolve ITP or AIHA. More recently, we
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have used rituximab in standard doses, for more refractory or recurrent ITP
and/or AIHA with success in 11 patients with CVID (unpublished).
Splenectomy is to be avoided in CVID as severe infections have occurred, as
we and other have shown(5, 50), although this is not found in all series(48).
Other autoimmune diseases also occur in CVID, including pernicious anemia,
rheumatoid arthritis, Sjogren's syndrome, vasculitis, thyroiditis, alopecia,
vitiligo, hepatitis, primary biliary cirrhosis, uveitis, sicca syndrome and systemic
lupus erythematosus; the treatment for these is standard therapy.
Cancer, Lymphoid hyperplasia, splenomegaly, and lymphoma: The
incidence of malignancy appears overall increased in CVID, occurring in up to
15% of subjects. In a 1985 study of 220 patients, a five-fold increase in cancer
was found due mostly to excesses of stomach cancer (47-fold) and non
Hodgkin’s lymphoma (30-fold)(51). For 176 subjects in a European study, the
observed to expected ratio for lymphoma in CVID was 12.1 and for stomach
cancer was 10.3 (52). Zullo et al found H Pylori in 14 of 34 subjects with
gastric symptoms, one of whom had gastric cancer, suggesting a potentially
causative role (53). However, suggesting a potential downward trend of this
cancer, in our current cohort of 476 patients, there have been 3 stomach
cancers (0.6%) in contrast to 32 non-Hodgkin’s lymphomas (6.7%) and 4
cases of Hodgkin’s disease (Table 4).
Cervical, mediastinal and abdominal lymphoid hyperplasia and enlarged
spleen are found in at least 20% of CVID subjects. Lymphoid infiltrates occur
lung or other organs such as the liver or kidneys. Biopsies of lymph nodes
usually show atypical lymphoid hyperplasia, reactive lymphoid hyperplasia, or
granulomatous inflammation. In most cases no specific treatment is required
unless pulmonary involvement or other organ involvement impairs functions.
Splenomegaly can massive and yet not cause clinical symptoms. It is not my
practice to suggest or endorse splenectomy for any reason unless there is
marked hypersplenism, uncontrollable autoimmunity, or a real possibility of
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lymphoma. When there is doubt about the nature of an infiltrate, nodule, or
enlarged node, I request biopsy and histologic staining, also studies using a
standard panel of monoclonal markers appropriate for lymphoma. Enlarged
lymph nodes usually show atypical or reactive hyperplasia, with or without
preservation of germinal center boundaries; granulomatous infiltrations are
found in some(54). There is a typical lack of plasma cells in lymph nodes or
other lymphoid tissues in CVID (55). We also save tissue for Epstein-Barr
encoded RNAs (EBER) by in situ hybridization, cytogenetics and studies of B
and T cell clonality by molecular analysis. However, the presence of clonal
lymphocytes is not diagnostic as these can be found in biopsies showing
reactive hyperplasia but no evidence of lymphoma (56, 57).
When lymphomas appear in CVID, they are usually extranodal, B cell in type,
and, unlike lymphomas in other congenital immune defects, are more common
in subjects in the 4th to 7th decade of life and usually EBV negative(5) (58) (47).
The median age at diagnosis of CVID in our cohort was 44; the median age at
death of lymphoma, was 59. Lymphoproliferative disease was diagnosed
mostly the 5th decade but the range was between age 13 to 88. In our
experience, females appear more likely to develop lymphoma than males; of
our current group of patients with lymphoid malignancies (72%) are female. A
number of cases of marginal zone (MALT) lymphomas have been reported
(59), in some cases related to H pylori (60). Lymphoma may be more likely to
arise in subjects with pre-existing polyclonal lymphoproliferation, as shown for
10 cases in 334 CVID subjects extracted from the previously established
European Society for Immune Deficiency (ESID) Registry (61) (62) (1). In this
study, a higher baseline serum IgM in CVID was correlated with both lymphoid
hyperplasia and lymphoma(1). The lymphomas in CVID appear to respond to
standard chemotherapy and rituximab protocols. However, it should be noted
that two female patients with MALT lymphomas (diagnosed 2 to 8 years
previously) that we follow, are entirely stable, and have not yet been treated.
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Gastrointestinal Disease: The main gastrointestinal manifestation of CVID is
transient or persistent diarrhea, found in 21- 57% of subjects (63-65). When a
cause is identified, G lamblia is the commonest organism; treatment with
metronidazole is generally effective but may require several courses. Other
pathogens can also be identified, including Cryptosporidium parvum,
cytomegalovirus, Salmonella species, Clostridium difficile, and Campylobacter
jejuni(66) . Helicobacter pylori infection has been associated with gastritis(53).
Aside from bacterial and parasitic infections, inflammatory bowel disease
remains a significant problem in 19%-32% (6, 65). Dissecting infectious from
inflammatory disease is not always simple; both can lead to chronic even
severe diarrhea, characterized by weight loss, steatorrhea and
malabsorption(5). On biopsy, the gastrointestinal mucosa contains excess
intraepithelial lymphocytes, villous blunting, lymphoid aggregates, granulomas,
crypt distortion, and as noted above, a characteristic lack of plasma cells(64,
65). Another common feature is villous flattening in the small intestine,
suggesting celiac sprue. However we have not found wheat withdrawal to be
beneficial and instead leads to additional weight loss. In the worst cases,
significant loss of essential nutrients (e.g. calcium, zinc, and vitamins A, E and
D) leads to bone loss and neurological deficits, which are not easily
reversed(67). Nodular lymphoid hyperplasia (containing an expanded number
of B cells but no plasma cells) is common, may be observed on endoscopy in
any area of the GI tract; when massive, this can lead to both severe chronic
diarrhea and weight loss (Figure 2). Initial treatment is based on culture
results, biopsy findings, and usually includes antibiotics, restoration of
nutrients and rehydration.
The management of inflammatory bowel disease in CVID is the same as for
immunocompetent patients, including antibiotics, such as metronidazole or
tinidizole or ciprofloxacin, 5-aminosalicylic acid and/or non-absorbed oral
steroids such as budesonide. Low-dose corticosteroids such as prednisone
can be used in doses of 10 mg/day; however, higher doses can lead to a
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significant risk of infections. Immunomodulators, such as azathioprine or 6-
mercaptopurine, can be used safely as the doses used (as for Crohn’s
disease) are low and do not appear to affect standard T- and B-cell function
tests (66). Infliximab has also been used with some benefit in severe
enteropathy (68).
Excluding HCV or any other persistent virus, liver disease, including primary
biliary cirrhosis and what appears to be autoimmune hepatitis, also occurs in
CVID. These lead to persistently increased liver enzyme levels; 43% of one
cohort had abnormal liver function tests, predominantly increased alkaline
phosphatase. Nodular regenerative hyperplasia leading to portal
hypertension and cholestasis is a complication increasingly recognized in
CVID, found in 14 of 40 subjects in a cohort of subjects who had these
abnormalities in liver function tests (69) (70).
Organ and Stem cell Transplantation in CVID: There are a few reports of
liver and lung transplant in CVID, with at least short term survival but overall
variable outcome (71, 72) (73). What has not been clarified, is with what
complications and at what stage, stem cell or bone marrow transplantation
should be considered in CVID. This question is most likely to arise when
severe immune compromise has been already documented and T cell
immunity is impaired. These cases resemble a form of combined immune
deficiency, and hypomorphic defects of genes known to cause SCID
(adenosine deaminase, Artemis or RAG1 or RAG2, and likely others (74-76))
should be sought. Unfortunately, here is little if any published information on
stem cell transplant in well-described CVID patients.
Genetics: Only some of the genetics leading to the CVID phenotype have
been clarified. These include several very rare recessive mutations: in the T
cell inducible co-stimulatory, ICOS in one kindred(77), mutations in CD19 in a
few unrelated families(78),(79) BAFF receptor in two siblings(80), CD20 and
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CD81 in one patient each (81, 82). As these are very rare events and not
found in general populations of patients, requesting these genetic tests in a
workup is not recommended. More promising, but from a research point of
view, has been work that identified mutations in transmembrane activator and
calcium-modulating cyclophilin ligand interactor (TACI, TNFRSF13B) in about
8% patients(83-85). Two of these, an extracellular mutation C104R and a
transmembrane mutation, A181E account for most of these. C104R leads to a
disruption of a region important for binding the ligands, B cell activating factor
(BAFF) and another soluble ligand, a proliferation inducing ligand (APRIL); the
transmembrane or intra-cytoplasmic mutations are presumed to lead to
impaired BAFF and APRIL signaling. In all studied populations, heterozygous
are far commoner than homozygous mutations and we and others have found
that these are associated with both autoimmunity and lymphoid hyperplasia.
Whether this is due to the generation of abnormal signals or haplo-
insufficiency, has not been clarified (86, 87). However, since the same
mutations are routinely found in normal family members and sometimes in
normal blood donors, testing for TACI mutations in patients is neither
diagnostic of CVID nor predictive of immune deficiency in the future. For this
reason, I do not recommended it for either of these purposes.
Survival, Clinical phenotypes and Biomarkers: In an earlier report on CVID,
56 of 248 (23%) of subjects died over a follow-up period of 1-20 years (mean
7.5 years.) Compared to age-matched controls, the survival was significantly
reduced, males at 64% as compared to 92% for controls, and 67% for
females, with controls expecting 94% survival for the same periods of time(5).
These outcomes were similar to a report of 240 patients in the United
Kingdom(4) in which over a 25 year period, 30% of subjects died.(5) The main
causes of death in both studies include chronic respiratory tract insufficiency,
destructive granulomatous organ involvement, liver disease, malnutrition due
to gastrointestinal pathology, uncontrolled autoimmune disease and lymphoma
(1, 9).
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In more recent years the overall survival of subjects with CVID appears
improved, very likely due to the now standard doses of replacement Ig. Of the
334 CVID subjects collected from the ESID Registry, 51 subjects (15%) died
over a longer mean follow-up period (22.5 years.) However, other factors
appear important in survival as revealed by examination of these data. While
about half of the patients had infections as the only manifestation, others with
one or more of the other complications outlined above (autoimmunity,
gastrointestinal disease, lymphoid hyperplasia, splenomegaly, granulomatous
disease, cancer or non–Hodgkin’s lymphoma) had diminished survival(1).
While a very low initial serum IgG level might be the most logical predictor for
complications, there was no association found between the level of the serum
IgG level at diagnosis and severe infections (including pneumonia), a higher
incidence of lung disease, or increased mortality. Strangely, neither age at
onset of symptoms, age at diagnosis, nor length of diagnostic delay was
related to increased mortality.
These registry data illustrate the need for additional biologically relevant
biomarkers to guide both evaluation and treatment in CVID. Previous studies
showed that poorer T cell functions, reduced lymphocyte counts, very low
numbers of B cells, and reduced numbers of both CD4+ T cells, and
CD45RA+CCR7+CD4+T(88) cells are associated with both opportunistic
infections and reduced survival (10) (5, 88). More recently, other studies have
suggested that the numbers and phenotypes of peripheral blood B cells are
useful biomarkers. CD27+ B cells but especially IgD-CD27+ isotype-switched
memory B are decreased(89) (90, 91) (92), and both we and others found that
CVID subjects with the fewest switched memory B cells produce less IgG
antibody after vaccine challenge(93) (94). In our studies, <0.5% isotype-
switched memory B cells is very significantly associated with autoimmunity,
granulomatous disease, hypersplenism, and lymphoid hyperplasia. We also
found that females with CVID have significantly more IgM+CD27+ memory
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cells and IgD-CD27+ cells than males, which suggests to us interesting
difference between sexes in CVID(36). We have not been able to verify that
CVID patients who have significantly lower numbers of circulating IgM+CD27+
memory B cells are more likely to develop chronic lung disease as previously
suggested (95) (96). Other suggested markers include reduced Tregs(97),
very low CD21+ B cells (92) and high levels serum BAFF and APRIL (98)
which might be associated with selected clinical conditions such as
autoimmunity and lymphoid hyperplasia.
Monitoring patients over time: Most patients with CVID carry out all normal
activities; many are treated on home care programs for years. While these
improvements represent ongoing advances in medical care, regularly
scheduled and careful follow-up is still mandatory as new problems may arise
or evolve over time. Stable patients must be seen at least yearly intervals,
those with the above complications at shorter intervals such as 3 to 6 months.
Table 5 outlines a suggested template for monitoring patients. Routines to
monitor subjects for and with lung disease have been controversial and there
is no current consensus. Chest X-rays are not as revealing as HRCT, so it is
reasonable to obtain this at baseline referral. However, radiosensitivity has
been demonstrated in CVID (99, 100), and for a younger subject, yearly or
every 2-year examinations, especially in concert with other X-ray procedures,
could lead to excessive radiation exposure over time(101). For more frequent
follow-up of patients with chronic cough and/or known lung damage, I prefer
complete lung functions including carbon monoxide (CO) diffusion as a means
of assessing lung damage at shorter intervals, with possible HRCT at 3-4 year
intervals or at less frequent intervals to monitor changes in therapy. Monitoring
for autoimmunity is not required as routine blood counts and general medical
oversight will reveal characteristic symptoms. Gastrointestinal diseases will be
similarly evident with complaints of diarrhea and often, weight loss. Loss of
height may reflect loss of bone density, especially prevalent in women with
CVID with any degree of deficiency or calcium loss; this requires reconstitution
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with vitamin D, calcium and other standard therapies. Routine endoscopy is
not required although patients with suggestive gastrointestinal symptoms
should have appropriate upper and/or lower endoscopy with examination for H
Pylori or other mucosal changes.
The issue of enlarged lymph nodes is always troublesome. When new nodes
appear and persist, biopsy may be required; however, in most cases,
lymphomas are extra nodal and appear in unusual locations such as lung or
mucosal associated tissues, and are thus not amenable to any standard
follow-up measures. In my experience, bone marrow examinations to seek
lymphoma also have not been positive, except in the most advanced cases,
where the diagnosis was already known.
Conclusions: Over the past three decades, the outlook for patients with CVID
has greatly improved due to standard Ig replacement therapy and more
effective antibiotic coverage. While it is disturbing to note that even in the most
recent surveys, the diagnosis is still delayed 6 to 8 years after the first
characteristic symptoms, most patients now go to school or work and are not
significantly disabled. Perhaps because infections are not as prominent,
morbidities globally ascribed to inflammation or immune dysregulation, have
become the areas of main medical concern. From the research point of view,
CVID represents a promising model to better understand mediators of immune
function and inflammation as well as the still relatively uncharted genetics of
antibody production.
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Acknowledgments:
This work was supported by grants from the National Institutes of Health, AI
101093, AI-467320, AI-48693, NIAID Contract 03-22, and the David S
Gottesman Immunology Chair.
Authorship:
Charlotte Cunningham-Rundles wrote this manuscript.
Conflict of Interest Disclosure:
Baxter Healthcare supports an ongoing research study at Mount Sinai, on the
demographics of immune deficiency in New York State, using de-identified data
and ICD coding.
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91. Piqueras B, Lavenu-Bombled C, Galicier L, Bergeron-van der Cruyssen F, Mouthon L, Chevret S, et al. Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J Clin Immunol 2003;23(5):385-400. 92. Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood 2008;111(1):77-85. 93. Ko J, Radigan L, Cunningham-Rundles C. Immune competence and switched memory B cells in common variable immunodeficiency. Clin Immunol 2005;116(1):37-41. 94. Alachkar H, Taubenheim N, Haeney MR, Durandy A, Arkwright PD. Memory switched B cell percentage and not serum immunoglobulin concentration is associated with clinical complications in children and adults with specific antibody deficiency and common variable immunodeficiency. Clin Immunol 2006;120(3):310-8. 95. Carsetti R, Rosado MM, Donnanno S, Guazzi V, Soresina A, Meini A, et al. The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency. J Allergy Clin Immunol 2005;115(2):412-7. 96. Detkova D, de Gracia J, Lopes-da-Silva S, Vendrell M, Alvarez A, Guarner L, et al. Common variable immunodeficiency: association between memory B cells and lung diseases. Chest 2007;131(6):1883-9. 97. Melo KM, Carvalho KI, Bruno FR, Ndhlovu LC, Ballan WM, Nixon DF, et al. A decreased frequency of regulatory T cells in patients with common variable immunodeficiency. PLoS One 2009;4(7):e6269. 98. Knight AK, Radigan L, Marron T, Langs A, Zhang L, Cunningham-Rundles C. High serum levels of BAFF, APRIL, and TACI in common variable immunodeficiency. Clin Immunol 2007;124(2):182-9. 99. Palanduz S, Palanduz A, Yalcin I, Somer A, Ones U, Ustek D, et al. In vitro chromosomal radiosensitivity in common variable immune deficiency. Clin Immunol Immunopathol 1998;86(2):180-2. 100. Vorechovsky I, Scott D, Haeney MR, Webster DA. Chromosomal radiosensitivity in common variable immune deficiency. Mutat Res 1993;290(2):255-64. 101. Fazel R, Krumholz HM, Wang Y, Ross JS, Chen J, Ting HH, et al. Exposure to low-dose ionizing radiation from medical imaging procedures. N Engl J Med 2009;361(9):849-57.
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Table 1 Suggested template evaluation to verify lack of IgG antibody
Serum IgG under
150 mg/dl
Repeat serum immune globulins for verification; no
antibody testing required
Serum IgG
between 150 and
250 mg/dl
Repeat serum immune globulins for verification;
Consider testing antibodies to tetanus and diphtheria or
other protein based vaccines; optional, non conjugated
pneumococcal vaccine and test 4 weeks post
vaccination.
Serum IgG
between 250 and
450 mg/dl
Repeat serum immune globulins for verification. Test
antibodies to tetanus and diphtheria or other protein
based vaccines; also non conjugated pneumococcal
vaccine and test 4 weeks post vaccination.
Serum IgG
between 450
mg/dl and 600
mg/dl
Repeat serum immune globulins for verification. Test
antibodies to tetanus and diphtheria and also other
protein based vaccines ( measles mumps rubella, H
zoster) also non conjugated pneumococcal vaccine and
test 4 weeks post vaccination
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Table 2 Summary of Complications and Incidence*
Numbers Perce
Infections 428 90
Autoimmunity 97 25
Lung Impairment 88 24
Gastrointestinal disease 51 14
Malabsorption 31 5
Lymphoid malignancy 36 10
Previous Splenectomy 31 8
Granulomatous disease 31 8
Other Cancers 21 6
• Based on a cohort of 476 subjects
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Table 3 Hematologic Autoimmunity*
Condition Number Percent
Thrombocytopenia 44 9.0
Evans syndrome 11 2.3
Acute hemolytic anemia 8 2.0
Anti-IgA antibodies 6 1.0
Neutropenia 2 0.4
Pernicious anemia 2 0.4
• Based on a cohort of 476 subjects
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Table 4: Cancer in CVID*
Kind Number Percent#
Non Hodgkin’s
Lymphoma
32 6.7
Other cancers* 20 4.0
Hodgkin’s disease 4 0.8
Waldenstrom’s
macroglobulinemia
1 0.2
Aplastic anemia 2 0.2
* based on 476 subjects
# other cancers: breast 6; colon 3, gastric 3; mouth 2; melanoma 2; lung 1;
skin 1; ovary 1; vagina 1.
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Table 5: Suggested monitoring for patients with CVID*
Patients Type Interval
All Interval history,
Physical examination
height and weight
12 months
Complete blood counts:
Hgb, Hct, white blood cells
and differential, platelets,
and chemistry panel
including liver and kidney
functions; albumin
12 months
Serum IgG* 6 to 12 months or with
weight gain, pregnancy
Chest X ray Referral
Spirometry 12 months
With lung disease High Resolution Chest CT 3 – 4 years or after
change of therapy
Complete lung functions
with CO diffusion
12 months
With gastrointestinal
complications
Upper and/or lower
Endoscopy
Intervals as required for
optimum treatment
With evidence of
malabsorption including
loss of height; women
in particular
Bone density, evaluation of
nutrients
As dictated by the
therapy used
* consider adding also serum IgA or IgM if there is a question about the
stability of the diagnosis or onset of other complications.
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Figure legends:
Figure 1a: This is a 40 year old woman with gradually worsening severe lung
disease. CT of the chest revealed massive infiltrates composed of lymphocytic
collections and fibrotic scars.
Figure 1b: On biopsy, the infiltrating T cells in the lung, obliterating normal
architecture, were revealed as CD4+ by the brownish monoclonal peroxidase
conjugated monoclonal anti-CD4- staining pattern. (25x magnification)
Figure 2a: This is a 50 year old woman who had a history of a duodenal ulcer,
now resolved. She had a repeat gastroscopy for symptoms of gastritis; H
Pylori was not found. The mucosa of the stomach folds of this female patient
contained numerous lymphoid follicles.
Figure 2b: The jejunum of this 28 year old male patient contained massive
nodules of lymphoid hyperplasia; he had experienced 20 lb weight loss.
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